Acute episodes of hypoglycemia are associated with long-term neurological injury, and it has been suggested that the developing brain may be more sensitive to the adverse affects of hypoglycemia. Potential mediators of hypoglycemia in the brain include adenosine. However, our understanding of the role that adenosine plays in hypoglycemia-induced brain injury is limited, as is our understanding of the developmental susceptibility of the brain to hypoglycemic damage. We have recently found that acute hypoglycemia (1.5 mM; 27 mg/dl; 6-12 hrs) results in much more neuronal death in younger than in older animals. In addition, we find that blockade of A1 adenosine receptor (A1AR) action reduces hypoglycemia-induced neuronal death. We also find that hypoglycemia leads to both neuronal and oligodendrocyte injury, possibly due to perturbations in intracellular Ca2+ signaling. Based on these observations, we hypothesize (a) that the developing brain is especially sensitive to the adverse effects of low glucose levels, (b) hypoglycemia leads to increased AIAR action, resulting in neuronal and oligodendrocyte injury, and (c) A1AR antagonists will reduce hypoglycemic brain injury. To test these hypotheses, (1) we will examine the developmental susceptibility of the brain to hypoglycemic injury. (2) We will assess the roles of A1ARs in mediating hypoglycemic injury. (3) We will examine mechanisms of hypoglycemic injury in neurons, and (4) oligodendrocytes. In many previous studies of hypoglycemia, non-physiological paradigms have been used that include the combination of hypoxia and hypoglycemia, aglycemia, or extended hypoglycemia. Thus, to provide insights into the effects of hypoglycemia, we will examine responses to glucose levels associated with clinical hypoglycemia (0.75-3 mM), without hypoxia or other metabolic insults. We will also focus on short-term, low glucose exposure. We anticipate that these studies will yield new insights into the mechanisms of hypoglycemic brain injury and may lead to the development of practical strategies for reducing hypoglycemic brain injury.